Garko became an instant breakout star in Europe in 1966 in the successful Spaghetti Western starring alongside Anthony Steffen in Blood at Sundown. In this movie, he played an antagonist named Sartana. He would later play an unrelated protagonist named Sartana in the famous Sartana series of films. Other notable westerns he starred in were $10,000 Blood Money (1967) as an unofficial Django, Vengeance is Mine/$100,000 for a Massacre (1967), They Call Him Cemetery (1971) alongside William Berger as well as a supporting role in Bad Man's River with Lee Van Cleef. During this time he had achieved considerable fame in Germany, Italy, and Spain. Outside of the western genre, Garko starred in Five for Hell (1969) with frequent co-star Klaus Kinski, a small role in Waterloo as the brave and energetic French artillery commander Antoine Drouot, and The Heroes, both with Rod Steiger. He also starred in a highly memorable episode of Space: 1999 in 1975.

After appearing in Space: 1999 as Tony Cellini in the episode "Dragon's Domain", starting in the 80's Garko concentrated more on television, theatre, and TV commercials as quality roles in film became fewer and farther in between. Popular in Europe but little known in America, in an interview, Garko mentioned that he had turned down the lead role in Pretty Baby (1978 with Brooke Shields).

To this day, Garko has amassed a sizeable cult following of fans for being one of the premiere leading men of Spaghetti Westerns back in the 1960s.